Intestinal inflammatory condition as used herein refers to inflammatory bowel disease and inflammation linked to food intolerance or allergy.
Inflammatory bowel disease (IBD) refers to a group of diseases including both Crohn's disease and ulcerative colitis. The two diseases are often grouped together due to their similar pathogenesis and clinical manifestations. In the absence of invasive imaging studies, it is not possible to distinguish the two diseases which are often considered as a single disease in a number of publications and studies. Definitive diagnosis of either disease requires imaging studies such as endoscopy (either sigmoidoscopy or colonoscopy), double contrast barium enema, and computed tomography (CT) scan; combined with laboratory tests including complete blood counts to detect elevated leukocyte levels, erythrocyte sedimentation rates and serum albumin concentration.
Both diseases are chronic, relapsing/remitting inflammatory diseases of the gastrointenstinal tract. The regions of the gastrointenstinal tract that are most often affected by Crohn's disease are the small intestine and large intestine, also called the colon, including the rectum; however, Crohn's disease can affect the entire gastrointenstinal tract from the mouth to the anus. There may be single or multiple patches of inflammation. Ulcerative colitis affects only the large intestine. Inflammation and ulceration in ulcerative colitis are limited to the mucosal and submucosal layers, two innermost layers of the four layers of the large intestine. The inflammation and ulceration in Crohn's disease can extend through all layers of the intestinal wall in both the small and large intestines. Common symptoms of the diseases include diarrhea, abdominal pain, rectal bleeding and weight loss. Complications of Crohn's disease include intestinal abscesses, fistula, abnormal passage leading from one portion of the intestine to another and permitting passage of fluids or secretions, and intestinal obstructions. Typically, the course of both diseases is intermittent, with disease exacerbations followed by periods of remission. However, ulcerative colitis may be a single event, or continuous with unrelenting symptoms.
Although there are many choices for therapeutic interventions in IBD, many have undesirable side effects that make them less than ideal for treatment of chronic disease. For mild ulcerative colitis, orally or topically (i.e. enema) delivered aminosalicylates are typically the first line of treatment. The aminosalicylate class consists of agents that contain 5-aminosalicyclic acid (5-ASA), is one of the oldest anti-inflammatory compounds employed in IBD. Used in high doses, 5-ASAs can induce remission in acute attacks. Although commonly used for maintenance therapy, 5-ASAs have not been demonstrated to be effective in maintaining remission. Commonly used 5-ASA formulations include sulfasalazine, oral and topical mesalamine, olsalazine and balsalazide. Various formulations are modified to provide available active drug to the site of interest (e.g. small or large intestine). Side effects are however not uncommon with 5-ASAs.
Corticosteroids are among the most effective agents for inducing remission in IBD attacks and are typically the second therapeutic option upon failure of treatment with 5-ASAs. The compounds are delivered first either orally or rectally, with or without concomitant administration of 5-ASAs. Upon failure of oral delivery, the compounds are administered intravenously. Ideally, corticosteroids are used for only a short course of treatment and tapered off upon remission of disease. Corticosteroids commonly used for the treatment of IBD include prednisone, budesonide and hydrocortisone. The use of corticosteroids is limited by the number of severe and significant side effects associated with their use. Common side effects of short term use include insomnia, night sweats, mood changes and altered glucose metabolism. Prolonged maintenance therapy is typically reserved only for severe, refractory cases. Prolonged therapy can lead to adrenal atrophy, whereas abrupt cessation can cause adrenal insufficiency, hypotension, and even death. Other side effects include acne, abnormal fat deposition, excessive hair growth and osteoporosis. In Crohn's disease, corticosteroids can thwart the healing of fistula, exacerbating the disease state.
Individuals responding to oral or rectal corticosteroids are often placed on a maintenance dose of 5-ASA. However, some physicians provide no pharmacological interventions during periods of remission.
Individuals who require therapy with intravenous corticosteroids are typically maintained on an immunosuppressive agent such as 6-mercaptopurine and/or azathioprine, in combination with a 5-ASA. Parenteral nutrition is typically considered with such severe disease. When the patient does not respond to the above therapies, the immunosuppressant cyclosporine may be administered in an attempt to avoid surgery to remove the section of diseased intestine. Immunosuppressant interventions are not without undesirable side effects. 6-Mercaptopurine and azathioprine can cause fever, rash, nausea and headache, with more severe side effects including leucopenia, pancreatitis, severe infections and bone marrow suppression. Cyclosporine can have more severe side effects including paresthesias (abnormal sensations like burning or tingling), excessive hair growth, hypertension, tremor, renal insufficiency, headache and opportunistic infections.
Antibiotics, typically ciprofloxacin or metronidazole, are used as add on therapies to 5-ASA or corticosteroids, especially with patients with fistulizing or colonic disease. As with all of the other therapies, there are side effects of long term treatment with antibiotics.
Infliximab and adalimumab are currently the pharmacotherapy of last resort in inflammatory bowel diseases. Infliximab is a chimeric monoclonal antibody composed of 75% human and 25% mouse protein, whereas adalimumab is full humanized antibody. Infliximab and adalimumab are inhibitors of tumor necrosis factor-alpha (TNF-α), a potent inflammatory cytokine. The drug acts as a sink by binding both soluble and membrane bound TNF-α. By inhibiting an activator high in the inflammatory cascade, a number of inflammatory pathways can be inhibited. The drug is administered intravenously first for treatment and subsequently as a maintenance drug every eight weeks as indicated on the product label. However, as it is a biological agent, an immune response can limit utility of the drug.
Therefore, immunosuppressive agents are typically given in conjunction with infliximab maintenance therapy. As with all other therapies for inflammatory bowel diseases, there are substantial side effects of infliximab. TNF-α plays an important role in the eradication of neoplastic cells; therefore, its suppression can lead to opportunistic infections, malignancies and other complications, especially as a long term strategy.
Surgical interventions are a method of treatment of inflammatory bowel diseases, not a cure. Due to the chronic nature of IBD and the relatively early age of onset, multiple surgeries can be required over the lifetime of patients who are not responsive to pharmacological interventions. Removal of short portions of the intestine is possible without substantial side effects. However, removal of larger or multiple segments of the intestine can result in short bowel syndrome in which individuals are unable to absorb nutrients. Removal of portions of the large intestine can result in the need for colostomy or other further surgical procedures. Therefore, surgery is not a preferred method of treatment of inflammatory bowel diseases. Surgical interventions for the treatment of inflammatory bowel diseases can result in further disease. Upon complete removal of the colon, an ileal pouch may be constructed from the small intestine by the surgeon to allow removal of feces through the anus rather than requiring a permanent ostomy. Pouchitis is a non-specific inflammation of the ileal pouch which typically occurs within the first two years after reconstruction. Symptoms include steadily increasing stool frequency that may be accompanied by incontinence, bleeding, fever and/or a feeling of urgency. Of those who have ulcerative colitis, approximately 20 to 30 percent experience at least one episode. Antibiotics can be sufficient to treat pouchitis; however, other more aggressive therapies similar to those used in IBD are required.
Among the recent new therapeutic approaches for treating inflammatory bowel diseases, WO2007/027132 discloses a method for treating said diseases, comprising the administration of regulatory CD4+CD25+ T cells collected from sentinel nodes of the patient and expanded in vitro.
Another type of intestinal inflammatory condition is due to food intolerance or allergy. Humans rather frequently suffer from more or less severe allergic or intolerance reactions after consumption of dietary proteins. The prevalence of food allergy or intolerance is approximately 1-2% in adults and 6-8% in children. Food allergy or intolerance is mainly associated with a limited range of foodstuffs, mainly peanuts, tree nuts, hen's eggs, cow's milk, wheat (gluten), soybeans, fish and shellfish.
To date, no effective treatment of food allergy or intolerance is available. Most allergic or intolerant individuals adapt to their situation and avoid intake of foodstuffs to which they are allergic or intolerant. Therapies involving drugs, such as antihistamines, decongestants, or steroids, are available but only combat the symptoms of intolerance or an allergic reaction. They do not prevent that future exposure to the allergen or dietary proteins causes new allergenic reactions or new intolerance.
In the present invention, the Applicant thus aims to provide a treatment for intestinal inflammatory condition based on the use of Tr1 cells, which are different from regulatory CD4+CD25+ T cells.
Groux et al (Nature 1997, 389:737-742) described that transfer of antigen (ovalbumin)-specific Tr1 cells prevents intestinal bowel disease induced by pathogenic CD4+CD45RBhigh T cells in mice, only when said Tr1 cells are stimulated in vivo by the antigen (in this case, by feeding the mice with ovalbumin). In addition, Foussat et al. (Journal of Immunology 2003, 171:5018-5026) described that co-administration of antigen (ovalbumin)-specific Tr1 cells and the antigen (ovalbumin in the drinking water) cures ongoing inflammatory bowel disease in mice. Co-administration of the antigen was a necessity for the Tr1 cells to be efficient.
According to the invention, the inventors aim to provide a treatment for an intestinal inflammatory condition in a subject in need thereof, said treatment being based on the unique administration of Tr1 cells directed against a food antigen from common human diet. In particular, the inventors surprisingly found that said Tr1 cells directed against a food antigen from common human diet do not need to be co-administrated with the food antigen from common human diet to be efficient.